The overall research focus of the collaborative team from the University of Illinois and The Ohio State University has been to determine the impact of tomatoes and their bioactive components, especially lycopene, on prostate carcinogenesis. Prostate cancer is the most common cancer in American men and dietary approaches that reduce risk, or delay onset, would have profound impact on public health. Epidemiological and animal studies suggest that consumption of tomato products reduces the risk of prostate cancer. We propose to carry out studies in transgenic mice to determine if the tomato carotenoids, lycopene, phytoene, and phytofluene, or their metabolic products reduce the risk of development and progression of prostate cancer. In order to answer the questions raised in this proposal, we will utilize two new mouse strains that lack one of the two known mammalian carotenoid cleavage enzymes, carotenoid 15, 15'monooxygenase (CMO-I) and carotenoid 9', 10'monooxygenase (CMO-II). The three major specific aims are: 1) delineate the tissue-specific expression of CMO-I and CMO-II in A) wild-type, CMO-I knockout (KO), and CMO-II KO mice in response to short (3 days) and long term (30 days) feeding of different levels of tomato powder or lycopene, and in B) TRAMP mice during the development of carcinogenesis, 2) precisely determine how changes in CMO-I and CMO-II expression dictate A) tissue biodistribution of tomato carotenoids, and B) production of lycopenoids and other tomato carotenoid metabolites, and 3) to investigate the effect of altered tomato carotenoid metabolism on prostate cancer by A) creating double transgenic mice and B) differentiating the ability of dietary tomato powder and lycopene to inhibit prostate cancinogenesis in TRAMP, TRAMP X CMO-I KO, and TRAMP X CMO-II KO mice. We are uniquely qualified to carry out the proposed studies due to our broad expertise with carotenoids and cancer models, access to CMO-I KO and II KO mice, and our ability to biosynthesize radiolabeled tomato carotenoids using tomato cell suspension culture. Our continuing hypothesis is that genetic polymorphisms involved in metabolism of carotenoids, such as CMO-I and II, are critical determinants of the benefits of tomato products against prostate carcinogenesis in humans. These studies will allow us to determine if tomato carotenoids, or their metabolic products, are able to prevent or counteract the development of prostate cancer.